A common class of chemicals found everywhere from car exhausts, smoke, building materials and furniture to cosmetics and shampoos could increase cancer risk because of their ability to break down the repair mechanisms that prevent faults in our genes, according to a study published today in the journal Cell.
Damage to our DNA arises frequently as our cells divide, and it can lead to the development of cancers. Fortunately, the body has its own defense mechanism that helps repair this damage. This defense mechanism, however, is obstructed by chemicals of the aldehyde class. According to a new study, aldehyde exposure impedes DNA repair, even in normal healthy cells, but people who have inherited a faulty copy of BRCA2 are particularly sensitive to such damage.
The study was led by Ashok Venkitaraman, Ph.D., director of the Medical Research Council Cancer Unit at the University of Cambridge. Prof. Venkitaraman and colleagues used genetically engineered human cells and cells from patients bearing a faulty copy of the breast cancer gene BRCA2 to identify the mechanism by which exposure to aldehydes could promote cancer.
Details of this work appeared June 1 in the journal Cell, in an article entitled “A Class of Environmental and Endogenous Toxins Induces BRCA2 Haploinsufficiency and Genome Instability.” The article reports that exposure to naturally occurring concentrations of formaldehyde or acetaldehyde selectively unmasks genomic instability in cells heterozygous for multiple, clinically relevant, truncating BRCA2 mutations.
“Naturally occurring concentrations of formaldehyde, a product of cellular metabolism and a ubiquitous environmental toxin, provoke replication fork instability and structural chromosomal aberrations in cells heterozygous for multiple, pathogenic truncating mutations affecting the BRCA2 tumor suppressor,” wrote the article’s authors. “These anomalies arise from a previously unrecognized effect of formaldehyde to selectively deplete BRCA2 via proteasomal degradation. … Similar effects occur with acetaldehyde, a product of ethanol catabolism.”
These findings could help explain why people who inherit a single faulty copy of the BRCA2 gene are susceptible to cancer. Cells should be able to repair DNA using the lower—but still adequate—levels of BRCA2 protein made from the remaining intact copy of the gene. But that doesn’t always happen.
This new study shows that aldehydes trigger the degradation of BRCA2 protein in cells. In people who inherit one faulty copy of the BRCA2 gene, this effect pushes down BRCA2 protein levels below the amount required for adequate DNA repair, breaking down the normal mechanisms that prevent mutations, which could promote cancer formation. The authors of the Cell article speculate that BRCA2 inactivation triggers spontaneous mutagenesis during DNA replication via aberrant RNA–DNA hybrids (R-loops).
“Our study shows how chemicals to which we are increasingly exposed in our day-to-day lives may increase the risk of diseases like cancer,” said Prof. Venkitaraman. “It also helps to explain why ‘the faults in our stars’—namely, the faulty genes we are born with—could make some people particularly sensitive to the cancer-causing effects of these chemicals.
“An important implication of our work is that it may be aldehyde exposure that triggers cancer susceptibility in people who inherit one faulty copy of the BRCA2 gene. This may help us in future to prevent or treat cancer in such people.”
Around one in 100 people may carry a faulty BRCA2 gene, putting them at risk of developing breast, ovarian, prostate, and pancreatic cancer. Exposure to aldehydes could increase their chances of developing these cancers.
Aldehydes are a class of chemicals made in our own bodies in small quantities. These chemicals, however, are increasingly prevalent in our environment. One common potential source of aldehydes is alcohol: our body converts the alcohol that we drink into acetaldehyde. Ordinarily, this is broken down by a natural enzyme known as acetaldehyde dehydrogenase, but over 500 million people, mainly from countries such as Japan, China, and Korea, inherit a faulty gene, ALDH2, that inactivates this enzyme. This is why many Asian people develop flushes when they drink, but could mean they are also particularly sensitive to the cancer-promoting effect.
This new research shows that aldehyde accumulation in such people could trigger cancer susceptibility by degrading BRCA2, compromising DNA repair, whether or not they inherit a faulty copy of BRCA2. An estimated 30% to 60% of people from Japan, Korea, and China carry the faulty ALDH2 and may therefore be at risk from cancer through this new mechanism.
“Epidemiological studies seem warranted to investigate the risk of cancer associated with BRCA2 mutations in such populations, particularly in light of the difficulty in testing these hypotheses in genetically engineered pre-clinical mouse models,” the authors of the Cell article noted. “Conversely, it is tempting to speculate that dietary supplementation with formaldehyde scavengers like Resveratrol may offer a future strategy to reduce cancer incidence in patients who carry pathogenic truncating mutations affecting BRCA2.”